Substituted quinolizine oximes and process for their production



United States Patent 3,326,920 SUBSTITUTED QUINOLIZINE OXIMES ANDPROCESS FOR THEIR PRODUCTION Robert J. Stanaback, Morristown, Richard E.Brown,

Hanover, and Robert I. Meltzer, Rockaway, N.J., assignors toWarner-Lambert Pharmaceutical Company, Morris Plains, N.J., acorporation of Delaware No Drawing. Filed Apr. 27, 1965, Ser. No.451,306 8 Claims. (Cl. 260286) This invention relates to novelsubstituted quinolizines and more particularly it relates toquinolizines of the formula:

. R R4 I HO-N .wherein R and R each represents hydrogen, hydroxy .orlower alkoxy such as methoxy or methylene dioxy;

R represents hydrogen or lower alkyl of lto 6 carbon atoms such asmethyl or ethyl; R represents hydrogen,

.hydroxy or --OR in which R is an acyl radical of from .1 to 6 carbonatoms; R represents hydrogen, lower alkyl of l to 6 carbon atoms,alkenyl such as vinyl, allyl, and

the like, acyl such as acetyl, formyl, propionyl and the like, ,1

wherein R is hydrogen or lower alkyl of '1 to 6 carbon atoms; or R and Rtaken together with the carbon atom to which they are attached representa keto or cyclic ketal group such as 1 and n is an integer of from 1 to2.

The symbols R R ,'"R R R5 and n as used hereinafter have the samemeaning as defined. v p

This invention also-encompasses within its scope a novel process for theproduction of the above compounds as well as intermediates useful fortheir production.

The compounds of this invention exhibit interesting steriodal activitiesand aretherefore useful in endocrine therapy. They also exhibitsignificant pharmacological activity on the cariovascular system, andanti-inflammatory activity. In use these compounds are combined with anontoxic pharmaceutical carrier to form dosage forms such as tablets,suspensions, elixir s, capsules and the like. They may also be combinedwith other therapeutic agents such as analgesics, antibiotics,cardiovascular agents, tranquilizers or muscle relaxants to enhance andbroaden their 3',326,920 Patented June 20, 1967 therapeutic spectrum. Inaddition, they are useful as intermediates for the production of othersubstituted quinolizines such as ll-amino substituted quinolizines.

The numbering of the compounds of this invention when n is 2 is asfollows:

According to the process of this invention these novel compounds areprepared by reacting a quinolizine of the formula:

"with nitrosyl chloride to give an intermediate of the formula:

The above intermediate II undergoes rapid tautomeri-- The startingquinolizine used in this reaction is described and prepared inaccordance with the process set' forth in application Ser. No. 248,872filed Jan. 2, 1963. The starting materials for these quinolizines areketo lactams of Formula C below. These are prepared from R and Rsubstituted I'phenylalkylamines of the general Formula A below andsubstituted ketoacids of the general Formula B in accordance with theprocess described in our copending application Ser. No. 318,190, filedOct. 23, 1963. The R, and R substituted phenylalkylamines such as3,4-diethoxyphenylethylamines are well known compounds which aredescribed in the literature, for example in Chemical Abstracts, vol. 56,page 10006 and by Ide et al. in J.A.C.S., vol. 59, page 726 (1937). WhenR and R are methylene dioxy, homopiperonylamine is used as startingmaterial. This is described in Dictionary of Organic Compounds, OxfordUniversity Press, 4th Edition, vol. I at page 132.

The ketoacids of Formula B are prepared according to the processdescribed in our copending application Ser. No. 310,146, filed Sept. 19,1963, using 2-R -cycloalkane- 1,3-diones as starting material. Such 2-R-cycloalkane- 1,3-diones are well known in the art and may be preparedaccording to the procedure of Panouse and Sannie published in Bull Soc.Chim. France, 1955, page 1036. See also H. Smith, I.C.S. 1964, page4472.

l R1 TH:

l (0 K coon Br I N H R:-

The keto lactam C is then treated with phosphorous oxychloride asdescribed in said application Ser. No. 248,872.

The above-described nitrosation reactions of this invention are bestcarried out at low temperatures in inert solvents. A temperature rangeof from 30 C. down to l20 C. will suffice, however, the preferabletemperature range is 50 C. to -78 C. Inert solvents useful in thisreaction are, for example, ether, benzene, toluene, dichloromethane andthe like.

The reaction is most conveniently carried out by adding slowly asolution of one molar equivalent of nitrosyl chloride dissolved in theinert solvent to a rapidly stirring solution of the quinolizine base ina suitable inert solvent and at the proper temperature. Under suchconditions there is formed an immediate precipitate of adduct II, whichcan in some cases be removed by simple filtration. In other cases, theinitial adduct is obtained in a form unsuitable f-or filtration. In suchcases, the reaction product is best isolated by extraction with water,whereby the material is obtained in form III.

Finally, compounds of the type III may in turn be reduced to givesaturated quinolizines of type IV:

Such reduction reactions are best carried out through the use of acomplex alkali metal borohydride such as sodium or potassiumborohydride.

The following examples are included in order further to illustrate theinvention.

EXAMPLE 1 Trans-2,3,3a,5,6,1I,12,1Za-oczahydro-I1-ket0-8-meth0xy-1H-benz0[a]cyclopenla [flquino lizinium chloride oxime A solution of2.34 g. (9.1 mols) of trans-1,2,3,3a,5,6, 12,12a octahydro 8methoxybenzo[a]cyclopenta[f] quinolizine in 200 ml. of anhydrous etheris cooled to -78 C. and treated dropwise with stirring with a solutionof 0.067 g. of nitrosyl chloride in 100 ml; of anhydrous ether. Thethick paste of yellow solid is allowed to warm up to 20 C. withstirring. The solid is filtered and recrystallized from ethanol to givetrans-2,3,3a,5,6,11,12-

12a octahydro 11 keto-8-methoxy-1H-benzo[a1cyclopenta[f] quinoliziniumchloride oxime as yellow crystals,

M.P. 208-2l0 C.

EXAMPLE 2 Trans 2,3,3a,5,6,11,12,1Za-octahydro-II-keto-l-carbethoxy 8methoxy 12a-methyl-1H-benzo[a]cyclopenta [f] quinolizinium perchlorateoxime In the same way as described in Example 1, 2.82 g. of trans1,2,3,3a,5,6,12,12a octahydro 1-carbethoxy-8- methoxy 12 methylbcnzo[a]cyclopenta [f] quinolizine gives trans 2,3,3a,5,6,11,12,12a octahydro 11keto-1- carbethoxy 8 methoxy 12a methyl 1H benzo[a] cyclopcnta [f]quinolizinium perchlorate oxime by extraction of the ether suspension ofthe initial adduct with water and adding a slight excess of 10%perchloric acid solution. The product is recrystallized from ethanol andmelts at 198-200 C.

' EXAMPLE 3 Trans-1,2,3,3a,5,6,1 0b,] 1,12,12a-decahydr0-8-methoxybenzo[a] cyclop-enta [f] quinolizine-l 1 -one oxime A solution of 3.0 g. oftrans-2,3,3a-5,6,l1,12,12a-octa hydro 11 ketoS-methoxy-lH-benzo[a]cyclopenta[f] quinolizinium chloride oxime in ml.of ethanol is treated with 2.0 g. of potassium borohydride in smallportions over a period of 2 hours at 20-30 C. The mixture is filteredand the ethanol removed by distillation. The residue is partitionedbetween water and ether. The ether layer is dried over magnesium-sulfateand the ether removed. The solid residue is recrystallized fromacetonitrile to give trans-1,2,3,3a,5,6,10b,11,12,12a-decahydro 8methoxybenzo[a]cyclopenta[f]quinolizine-l1 one oxime as white crystals,M.P. -193C.

5 EXAMPLE 4 Trans ],2,3,3a,5,6,10b,11,12,12a decahydro I carbethoxy 8methox'y 12a-methylbenzo[a]cyclopenta [f] quinolizine-J I-one oxime Inthe same way as described in Example 3, 2.0 g. of trans2,3,3a,5,6,11,l2,12a octahydro 11 keto l-carbethoxy-8-methoxy 12a methyl1H benzo[a]cyclopenta[f] quinolizinium perchlorate oxime givestrans-1,2, 3,3a,5,6,1l,12,l2a decahydro 1-carbethoxy-8-methoxy-12a-methylbenzo [aJcyclopenta [f] quinolizine 11 one oxime as whitecrystals, M.P. 193-195 C. after recrystallization from ethanol.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

1. A compound of the formula and cyclic ketal and n is an integer offrom 1 to 2.

2. A compound of the formula wherein R and R each is a member selectedfrom the group consisting of hydrogen, hydroxy, lower alkoxy andmethylene dioxy; R is a member selected from the group consisting ofhydrogen, methyl and ethyl; R is a member of the group consisting ofhydrogen, hydroxy and OR in which R is acyl of a carboxylic acid and Rand R taken together with the carbon atoms to which they are attachedform a member of the group consisting of keto and cyclic ketal and n isan integer of from 1 to 2.

3. Trans 2,3,3a,5,6,11,12,12a octahydro ll keto- 1 carbethoxy 8 methoxy12a methyl 1H benzo [a] cyclopenta[f] quinolizinium perchlorate oxime.

4. Trans 1,2,3,3a,5,6,10b,11,12,12a decahydro 8- methoxybenzo [a]cyclopenta [f] quinolizine-l l-one oxime.

5. Trans 1, 2,3,3a,5,6,10b,11,12,12a-decahydro-1-carbethoxy 8 methoxy12a methylbenzo[a] cyclopenta [f]quinolizine-1 l-one oxime.

6. Trans 2,3,3a,5,6,11,12,12a octahydro 11 keto- 8 methoxy 1Hbenzo[a]cyclopenta[f]quinolizinium chloride oxime.

7. Process for the production of a compound of the formula:

wherein R and R each is a member selected from the group consisting ofhydrogen, hydroxy and lower alkoxy; R is a member selected from thegroup consisting of hydrogen, methyl and ethyl; R is a member of thegroup consisting of hydrogen, hydroxy and OR in which R is an acyl of acarboxylic acid; R is a hydrogen,

in which R, is hydrogen and R and R taken together with the carbon atomsto which they are attached form a member of the group consisting of ketoand cyclic ketal and n is an integer of from 1 to 2 which comprisescontacting a compound of the formula:

with nitrosyl chloride in an inert nonpolar solvent at low temperaturesto form an intermediate of the formula:

followed by recovering said intermediate from said solvent andcontacting said intermediate with water or lower molecular weightalcohol.

8. A compound of the formula:

.HCI

wherein R and R each is a member selected from the group consisting ofhydrogen, hydroxy and lower alkoxy; R is a member selected from thegroup consisting of hydrogen, methyl and ethyl; R is a member of thegroup consisting of hydrogen, hydroxy and OR in which R is an acyl of acarboxylic acid; R is hydrogen,

. 7 C-N and G-0R7 H ll' 0 R 0 in which R, is hydrogen and R and R takentogether with the carbon atoms to which they are attached form a memberof the group consisting of keto and cyclic ketal and n is an integer offrom 1 to 2.

ALEX MAZEL, Primary Examiner. DONALD G. DAUS, Assistant Examiner.

2. A COMPOUND OF THE FORMULA
 3. TRANS - 2,3,3A,5,6,11,12,12A -OCTAHYDRO - 11 - KETO1 - CARBETHOXY - 8 -METHOXY - 12A -METHYL -1H-BENZO (A)CYCLOPENTA(F)QUINOLIZINUM PERCHLORATE OXIME.